rs1128127

Positions:

• chr22-23836945-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001002862.3(DERL3):​c.632C>T​(p.Ala211Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,584,594 control chromosomes in the GnomAD database, including 23,167 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.23 (5575 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17592 hom.)
• Consequence: DERL3 NM_001002862.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.95

Genes affected

DERL3 (HGNC:14236): (derlin 3) The protein encoded by this gene belongs to the derlin family, and resides in the endoplasmic reticulum (ER). Proteins that are unfolded or misfolded in the ER must be refolded or degraded to maintain the homeostasis of the ER. This protein appears to be involved in the degradation of misfolded glycoproteins in the ER. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Oct 2008]

SMARCB1 (HGNC:11103): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.0331483E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DERL3	NM_001002862.3	c.632C>T	p.Ala211Val	missense_variant	7/7	ENST00000318109.12
SMARCB1	NM_003073.5	c.*2765G>A		3_prime_UTR_variant	9/9	ENST00000644036.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DERL3	ENST00000318109.12	c.632C>T	p.Ala211Val	missense_variant	7/7	1	NM_001002862.3	P1
SMARCB1	ENST00000644036.2	c.*2765G>A		3_prime_UTR_variant	9/9		NM_003073.5	A1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34194 AN: 151598 Hom.: 5559 Cov.: 32

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.214

GnomAD3 exomes AF: 0.166 AC: 35198 AN: 211492 Hom.: 4022 AF XY: 0.166 AC XY: 19072 AN XY: 115042

Gnomad AFR exome AF: 0.475

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.103

Gnomad SAS exome AF: 0.277

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.141 AC: 202528 AN: 1432878 Hom.: 17592 Cov.: 38 AF XY: 0.144 AC XY: 102353 AN XY: 710772

Gnomad4 AFR exome AF: 0.475

Gnomad4 AMR exome AF: 0.119

Gnomad4 ASJ exome AF: 0.159

Gnomad4 EAS exome AF: 0.0674

Gnomad4 SAS exome AF: 0.271

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.226 AC: 34240 AN: 151716 Hom.: 5575 Cov.: 32 AF XY: 0.224 AC XY: 16589 AN XY: 74144

Gnomad4 AFR AF: 0.460

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.277

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.212

Alfa AF: 0.148 Hom.: 4457

Bravo AF: 0.233

TwinsUK AF: 0.122 AC: 454

ALSPAC AF: 0.112 AC: 430

ESP6500AA AF: 0.456 AC: 2009

ESP6500EA AF: 0.126 AC: 1080

ExAC AF: 0.165 AC: 19961

Asia WGS AF: 0.200 AC: 698 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.76	D
MetaRNN	Benign	0.00040	T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.99	P;P;P;P
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.084
Sift	Benign	0.27	T
Sift4G	Benign	0.26	T
Polyphen		0.0070	B
Vest4		0.014
ClinPred		0.010	T
GERP RS		2.3
Varity_R		0.043

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1128127; hg19: chr22-24179132; COSMIC: COSV51956055; COSMIC: COSV51956055;